Ischemia comprises myocardial metabolism and its capacity to generate sufficient high-energy phosphate to maintain contractile function and viability. Although early recanalization has become the mainstay of treatment of acute, thrombotic coronary occlusion, salutary effects are limited by irreversible injury anteceding reperfusion. This project is designed to develop metabolic strategies which protect ischemic myocardium and thereby enhance the salutary effects of reperfusion. Studies will be performed in isolated perfused rabbit hearts and in intact, anesthetized dogs under conditions of myocardial ischemia and reperfusion with or without adjunctive agents that either enhance glycolysis or decrease accumulation of potentially deleterious long-chain acyl-carnitines. Effects will be evaluated and related to their ability to limit the extent of injury sustained and to favorably influence nutritive perfusion, myocardial metabolism and contractile function. Positron emission tomography (PET) will be used to sequentially follow the flow and metabolic effects. Specifically, H2(15)O will be used to assess myocardial perfusion, 1-(11)C-acetate for overall oxidative metabolism 1- (11)C-palmitate for long-chain fatty acid metabolism, and 1-(11)C-glucose will be used to evaluate overall glycolytic flux. In addition, the recently developed and validated blood oxygen level detection (BOLD) approach using magnetic resonance imaging (MRI), which assesses regional levels of myocardial oxygen saturation/desaturation will be used to sequentially follow myocardial ischemia (the imbalance between oxygen supply and demand irrespective of levels of absolute use). MRI will also be used for sequential assessment of regional function. A second aim of the proposed project is to continue to refine and validate physiologically based, mathematical models necessary to quantify myocardial perfusion and metabolism noninvasively with PET. The research performed should help delineate whether adjunctive pharmacological strategies can be employed to minimize ischemic injury and enhance the salutary effects of reperfusion through specific metabolic interventions, applicable ultimately to patients with transient myocardial ischemia.